Peripheral and Islet Interleukin-17 Pathway Activation Characterizes Human Autoimmune Diabetes and Promotes Cytokine-Mediated β-Cell Death
- Sefina Arif1,
- Fabrice Moore2,
- Katherine Marks1,
- Thomas Bouckenooghe2,
- Colin M. Dayan3,
- Raquel Planas4,
- Marta Vives-Pi4,
- Jake Powrie5,6,
- Timothy Tree1,
- Piero Marchetti7,
- Guo Cai Huang8,
- Esteban N. Gurzov7,
- Ricardo Pujol-Borrell5,
- Decio L. Eizirik2 and
- Mark Peakman1,6⇓
- 1Department of Immunobiology, School of Medicine, King’s College London, London, U.K.
- 2Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium
- 3Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, U.K.
- 4Laboratory of Immunobiology, Blood and Tissue Bank, Institut d’Investigacio Germans Trias i Pujol, Barcelona, Spain
- 5Department of Diabetes and Endocrinology, Guy’s & St Thomas’ Hospital National Health Service (NHS) Foundation Trust, London, U.K.
- 6National Institute for Health Research Biomedical Research Centre at Guy’s & St Thomas’ NHS Foundation Trust and King’s College London, London, U.K.
- 7Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
- 8Diabetes Research Group, School of Medicine, King’s College London, London, U.K.
- Corresponding author: Mark Peakman, .
OBJECTIVE CD4 T-cells secreting interleukin (IL)-17 are implicated in several human autoimmune diseases, but their role in type 1 diabetes has not been defined. To address the relevance of such cells, we examined IL-17 secretion in response to β-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for β-cells.
RESEARCH DESIGN AND METHODS Peripheral blood CD4 T-cell responses to β-cell autoantigens (proinsulin, insulinoma-associated protein, and GAD65 peptides) were measured by IL-17 enzyme-linked immunospot assay in patients with new-onset type 1 diabetes (n = 50). mRNA expression of IL-17A and IFNG pathway genes was studied by qRT-PCR using islets obtained from subjects who died 5 days and 10 years after diagnosis of disease, respectively, and from matched control subjects. IL-17 effects on the function of human islets, rat β-cells, and the rat insulinoma cell line INS-1E were examined.
RESULTS A total of 27 patients (54%) showed IL-17 reactivity to one or more β-cell peptides versus 3 of 30 (10%) control subjects (P = 0.0001). In a single case examined close to diagnosis, islet expression of IL17A, RORC, and IL22 was detected. It is noteworthy that we show that IL-17 mediates significant and reproducible enhancement of IL-1β/interferon (IFN)-γ–induced and tumor necrosis factor (TNF)-α/IFN-γ–induced apoptosis in human islets, rat β-cells, and INS-1E cells, in association with significant upregulation of β-cell IL17RA expression via activation of the transcription factors STAT1 and nuclear factor (NF)-κB.
CONCLUSIONS Circulating IL-17+ β-cell–specific autoreactive CD4 T-cells are a feature of type 1 diabetes diagnosis. We disclose a novel pathway to β-cell death involving IL-17 and STAT1 and NF-κB, rendering this cytokine a novel disease biomarker and potential therapeutic target.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1643/-/DC1.
- Received November 30, 2010.
- Accepted May 5, 2011.
- © 2011 by the American Diabetes Association.
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